Composition to enhance the bioavailability of curcumin

ABSTRACT

A composition for enhanced bioavailability of curcumin including purified curcuminoid and purified essential oil of turmeric. A method to prepare a composition for enhanced bioavailability of curcumin having purified curcuminoid and purified essential oil of turmeric.

RELATED APPLICATIONS

This Application is a continuation of U.S. application Ser. No.14/623,608 filed Feb. 17, 2015, which is a divisional of U.S.application Ser. No. 13/674,249 filed Nov. 12, 2012, which is adivisional of U.S. application Ser. No. 13/506,572, filed Apr. 30, 2012,which is a divisional of U.S. application Ser. No. 12/926,980, filedDec. 21, 2010, which is a divisional of Ser. No. 12/073,864, filed Mar.11, 2008, which is a continuation-in-part of Ser. No. 11/635,599, filedDec. 8, 2006, which is a continuation of PCT Application Serial No.PCT/IN05/00176, filed May 30, 2005; all of which applications areincorporated in their entirety by reference.

FIELD

This invention relates to a formulation of curcuminoid with essentialoil of turmeric to enhance the bioavailability of curcumin and toaugment the biological activity of curcumin, wherein curcumin is themain constituent of curcuminoid and wherein Ar-turmerone is the mainconstituent of the essential oil of turmeric. Such enhancedbioavailability of curcumin has been demonstrated in human volunteers.

BACKGROUND

Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione]

is the major yellow pigment of turmeric, a commonly used spice, derivedfrom the rhizome of the herb Curcuma longa Linn. In the Indiansubcontinent and Southeast Asia, turmeric has traditionally been used asa treatment for inflammation, skin wounds, and tumors. Clinical activityof curcumin is yet to be confirmed; however, in preclinical animalmodels, curcumin has shown cancer chemo preventive, antineoplastic andanti-inflammatory properties (for a review, see, Kelloff, G. I., et al,J. Cell Biochem., 1996, 265:54-71). Especially interesting is itsability to prevent the formation of carcinogen-induced intestinalpremalignant lesions and malignancies in rats (Rao, C. V. et al, CancerRes., 1995, 55:259-66; Kawamori, T. et al, Cancer Res., 1999,59:597-601), and in the multiple neoplasia (Min/+) mouse (Mahmood, N. N.et al, Carcinogenesis, 2000, 31:921-27), a genetic model of the humandisease familial adenomatous polyposis. Curcumin acts as a scavenger ofoxygen species such as hydroxyl radical, superoxide anion and singletoxygen (Subramanian, M. et al, Mutat. Res., 1994, 311:249-55; Tonnesen,H. H. et al, Int. J. Pharm., 1992, 87:79-87; Reddy, A. C. P. et al, Mol.Cell Biochem., 1994, 137:1-8) and interferes with lipid peroxidation(Donatus, I. A., Biochem. Pharmacol., 1990, 39:1869-75; Sharma, S. C. etal, Biochem. Pharmacol., 1972, 21:1210-14). Curcumin suppresses a numberof key elements in cellular signal induction pathways pertinent togrowth, differentiation and malignant transformations. Among signalingevents inhibited by curcumin are protein kinases (Liu, J. V. et al,Carcinogenesis, 1993, 14:857-61), c-Jun/AP-1 activation (Huang, T. S. etal, Proc. Natl. Acad. Sci., 1991, 88:5292-96), prostaglandinbiosynthesis (Huang, M-T. et al, In L. W. Battenberg (ed.) Cancer Chemoprevention, CRC Press, Boca Raton, 1992, pp 375-91) and activity andexpression of the enzyme cyclooxygenase-2 (Huang, M. T., et al, CancerRes., 1991, 51:813-19; Zhang, F. et al, Carcinogenesis, 1999,20:445-51). This latter property is probably mediated by the ability ofcurcumin to block activation of the transcription factor NF-κB at thelevel of the NF-κB inducing kinase/IKKα/β signalling complex (Plummer,S. et al, Oncogene, 1999, 18:6013-20).

Curcumin directly inhibits cyclooxygenase-2 and also inhibits thetranscription of the gene responsible for its production.Cyclooxygenases (COX) catalyze the synthesis of prostaglandins (PGs)from arachidonic acid. There are two isoforms of COX, designated COX-1and COX-2. COX-1 is expressed constitutively in most tissues and appearsto be responsible for housekeeping functions (Funk, C. D. et al, FASEBJ., 1991, 5:2304-12) while COX-2 is not detectable in most normaltissues but is induced by oncogenes, growth factors, carcinogens andtumor promoters (Subbaramiah, K. et al, 1996, Cancer Res., 1996,56:4424-29; DuBois, R. N. et al, J. Clin. Invest., 1994, 93:493-98;Kelley, D. J. et al, Carcinogenesis, 1997, 18:795-99). Several differentmechanisms account for the link between COX-2 activity andcarcinogenesis.

Curcumin is not simply an alternative to non-steroidal anti-inflammatorydrugs (NSAIDS), which also have anti-inflammatory and cancerchemopreventive properties. This is so because COX is a bifunctionalenzyme with cyclooxygenase and peroxidase activities. Aside from beingimportant for PG synthesis, the peroxidase function contributes to theactivation of procarcinogens. Therefore, the failure of NSAIDS toinhibit the peroxidase function of COX potentially limits theireffectiveness as anticancer agents. Curcumin, in contrast,down-regulates levels of COX-2 and thereby decreases both thecyclooxygenase and peroxidase activities of the enzyme.

Curcumin is among the few agents to block both the COX and LOX(lipoxygenase) pathways of inflammation and carcinogenesis by directlymodulating arachidonic acid metabolism. In a study to evaluate theeffect of curcumin on the metabolism and action of arachidonic acid inmouse epidermis, it was found that topical application of curcumininhibited arachidonic acid-induced ear inflammation in mice (Huang, M.T., et al Cancer Res., 1988, 48:5941-46; 1991, 51:813-19). Curcumin (10μM) inhibited the conversion of arachidonic acid to 5- and8-hydroxyeicosatetraenoic acid by 60% and 51%, respectively (LOXpathway) and the metabolism to PGE2, PGF2α and PGD2 by 70%, 64% and 73%,respectively (COX pathway). In another study, dietary administration of0.2% curcumin to rats inhibited azoxymethane-induced coloncarcinogenesis and decreased colonic and tumor phospholipase A2,phospholipase CγI, and PGE2 levels (Rao, C. V. et al., Cancer Res.,1995, 55:259-66). In this study, dietary curcumin also decreased enzymeactivity in the colonic mucosa and tumors for the formation of PGE2,PGF2α, PGD2, 6-keto-PGF2α and thromboxane B2 via the COX system andproduction of 5(S)-, 8(S)-, 12(S)-, and 15(S)-hydroxy-eicosatetraenoicacid via the LOX pathway was also inhibited.

Despite this impressive array of beneficial bioactivities, thebioavailability of curcumin in animals and man remains low. In rodents,curcumin demonstrates poor systemic bioavailability after p.o. dosing(Ireson, C. R. et al, Cancer Res., 2001, 41:1058-64) which may berelated to its inadequate absorption and fast metabolism. Curcuminbioavailability may also be poor in humans as seen from the results of arecent pilot study of a standardized turmeric extract in colorectalcancer patients (Sharma, R. A. et al, Clin. Cancer Res., 2001,7:1834-1900). Indirect evidence suggests that curcumin is metabolized inthe intestinal tract. Curcumin undergoes metabolic O-conjugation tocurcumin glucuronide and curcumin sulfate and bioreduction totetrahydrocurcumin, hexahydrocurcumin and hexahydrocurcuminol in ratsand mice in vivo (Pan, M. H. et al, Drug Metabol. Dispos., 1999,27:486-94; Asai, A., et al, Life Sci., 2000, 67:2785-93), in suspensionsof human and rat hepatocytes (Ireson et al, loc. cit) and in human andrat intestine (Ireson, C. R. et al, Cancer Epidemiol. Biomark. Prev.,2002, 11:105-11). Metabolic conjugation and reduction of curcumin wasmore in human than in rat intestinal tissue. It has been suggested thatthe intestinal tract plays an important role in the metabolicdisposition of curcumin. This is based predominantly on experiments inwhich [³H] labeled curcumin was incubated with inverted rat gut sacs(Ravindranath, V. and Chandrasekhara, N., Toxicology, 1981, 20:251-57).This was later confirmed in intestinal fractions from humans and rats.Intestinal mucosa, as well as liver and kidney tissue from the rat, canglucurodinate and sulfate curcumin, as judged by the analysis ofdifferential amounts of curcumin present before and after treatment oftissue extracts with conjugate-hydrolyzing enzymes (Asai et al, loccit). Thus, gut metabolism contributes substantially to the overallmetabolic yield generated from curcumin in vivo. In human intestinalfractions, conjugation with activated sulfuric or glucuronic acids wasmuch more abundant, whereas conjugation in human hepatic tissues wasless extensive, than in the rat tissues (Ireson, C. R., et al, CancerEpidemiol. Biomark. Prev., 2002, 11:105-11).

Although p.o. administered curcumin has poor bioavailability and onlylow or non-measurable blood levels were observed (Perkins, S. et al,Cancer Epidemiol. Biomark. Prev., 2002, 11:535-40), this route ofadministration inhibits chemically induced skin and liver carcinogenesis(Limtrakul, P., et al, Cancer Lett., 1997, 116:197-203; Chiang, S. E. etal, Carcinogenesis, 2000, 21:331-35). Oral administration of curcuminalso inhibits the initiation of radiation-induced mammary and pituitarytumors (Inano, H. et al, Carcinogenesis, 2000, 21:1835-41; Int. J.Radiat. Oncol. Biol. Phys., 2002, 52:212-23; ibid, 2002, 53:735-43).Similarly, in a study to assess the curcumin levels in the colorectum, adaily dose of 3.6 g curcumin achieves pharmacologically effective levelsin the colorectum with negligible distribution of curcumin outside thegut (Garcea, G. et al, Cancer Epidemiol. Biomark. Prev., 2005,14:120-25).

Earlier Shobha et al (Planta Med., 1998, 64:353-56) had observed thatadministering piperine along with curcumin enhances the bioavailabilityof curcumin. However, the level of enhancement was only modest and nocurcumin could be detected after 3 hours even when supplemented withpiperine.

SUMMARY

Thus, in order to derive full benefits from the administration ofcurcumin in human subjects, ways and means to enhance itsbioavailability needs to be explored. The present invention is an effortin this direction. It was found that if small percentages (˜5%) of theessential oil of turmeric was added to the curcuminoid, then thebioavailability of curcumin was significantly enhanced. Accordingly, acomposition of curcuminoid admixed with a suitable proportion ofar-turmerone (the main component of the turmeric essential oil) isprovided.

The disclosure provides a composition of a curcuminoid and an essentialoil of turmeric.

The disclosure provides a composition of a curcuminoid and an essentialoil of turmeric, wherein the curcuminoid includes curcumin.

The disclosure provides a composition of a curcuminoid and an essentialoil of turmeric, wherein curcumin comprises 95% of the curcuminoid.

The disclosure provides a composition of a curcuminoid and an essentialoil of turmeric, wherein a weight ratio of the curcuminoid to theessential oil of turmeric ranges from about 1:1 to about 99:1.

The disclosure provides a composition of a curcuminoid and an essentialoil of turmeric, wherein the essential oil is present in an amountsufficient to cause an enhancement of bioavailability of the curcuminwhen the composition is administered to a human as compared tobioavailability of the curcumin obtained upon administration of acomposition of curcuminoid that was prepared without adding essentialoil of turmeric. In some embodiments, the bioavailability of curcuminfrom the composition of curcumin and added essential oil of turmeric isat least 2-fold greater than the composition of curcuminoid without theadded essential oil of turmeric. The disclosure provides a compositionof a curcuminoid and an essential oil of turmeric, wherein theenhancement of bioavailability of the curcumin ranges from about 5-foldto about 16-fold.

The disclosure provides a method of extracting a curcuminoid fromturmeric including:

drying rhizomes of turmeric to form a dried turmeric;

powdering the dried turmeric to form a powdered turmeric;

treating the powdered turmeric with a solvent selected from the groupconsisting of ethyl acetate, acetone, hexane, ethylene dichloride, ethylalcohol, and combinations thereof to form a solution; stripping thesolvent from the solution to form an extract;

cooling the extract to about 4° C. to form crystals and a liquid,wherein the liquid comprises the essential oil of turmeric and a resin;and

separating the crystals from the liquid to obtain the curcuminoid, andwherein curcumin comprises 95% of the curcuminoid.

The disclosure provides a method of preparing a composition for enhancedbioavailability of curcumin having a curcuminoid and an essential oil ofturmeric including:

suspending the curcuminoid in water to form a suspension;

adding the essential oil to the suspension to form a mixture;

homogenizing the mixture to obtain a fine slurry; and

drying the fine slurry under heat and vacuum to form a uniform blend ofthe composition having the curcuminoid and the essential oil. Thedisclosure provides a method of preparing a gelatin capsule containing acomposition for enhanced bioavailability of curcumin having acurcuminoid and an essential oil of turmeric for oral administration toa human.

Curcumin levels in blood samples from 9 human volunteers was comparedfollowing administration of a composition of curcuminoid alone or acomposition of curcuminoid having added essential oil of turmeric. Bloodsamples were collected at zero hour and then at hourly or half-hourlyintervals up to 8 hours. Upon administration of a composition havingcurcuminoid and added essential oil of turmeric, maximum absorption wasobserved at 3 hours after ingestion and resulted in curcumin levels thatwere 5-16 fold higher compared to absorption of curcumin fromcurcuminoid capsules prepared without added essential oil of turmeric.In some embodiments, the bioavailability of curcumin from thecomposition of curcumin and added essential oil of turmeric is at least2-fold greater than the composition of curcuminoid without the addedessential oil of turmeric. In some embodiments, the bioavailability ofcurcumin from a composition of curcumin and added essential oil ofturmeric ranges from about 3-fold to about 16-fold greater thanbioavailability of curcumin from a composition of curcuminoid withoutthe added essential oil of turmeric.

With ar-turmerone as the adjuvant in Biocurcumax, wherein Biocurcumax isa composition having curcuminoid and added essential oil of turmeric,peak absorption occurred at 3 hours and persisted at low levels at leastuntil 8 hours, beyond which no measurements were made.

BRIEF DESCRIPTION OF THE DRAWINGS

The above objectives and advantages of the disclosed teachings willbecome more apparent by describing in detail preferred embodimentsthereof with reference to the attached drawings in which:

FIG. 1 provides a graph showing the bioavailability of curcumin inhumans upon administration of (1) Biocurcumax gelatin capsules, whichwere prepared by admixing curcuminoid isolated from turmeric withessential oil of turmeric, and, (2) gelatin capsules of curcuminoidalone, which were prepared without adding essential oil of turmeric tothe curcuminoid isolated from turmeric. The x-axis shows time in hoursfollowing administration of the gelatin capsules. The y-axis shows theconcentration of curcumin (ng/g) in blood.

DETAILED DESCRIPTION

The disclosure relates to a product to enhance the bioavailability ofcurcumin by mixing a suitable portion of the volatile oil obtained fromturmeric with the curcuminoids isolated from turmeric.

As disclosed herein the term “curcuminoid” is a mixture of curcumin,demethoxycurcumin and bisdidemethoxycurcumin, wherein curcumin is themajor component of the curcuminoid and comprises about 95% of thecurcuminoid, and, demethoxycurcumin and bisdidemethoxycurcumin are minorcomponents of the curcuminoid.

The term “essential oil” or “essential oil of turmeric” is also referredto as “volatile oil” or “volatile oil of turmeric.” The essential oil ofturmeric is a mixture of oils. Essential oil is obtained as a by-productduring the extraction of curcumin or curcuminoids from turmeric.Ar-turmerone, which is also referred to as turmerone, is the mainconstituent of essential oil. Ar-turmerone constitutes about 45% of theessential oil of turmeric.

As stated herein, the term “a” or “an” refers to one or more.

As stated herein, the terms “isolated” and “purified” are referred tointerchangeably.

The volatile oil of turmeric was isolated by conventional methods ofsteam distillation to isolate essential oils and is well known in theart.

Curcumin is isolated from the de-oiled turmeric by solvent extraction.Suitable solvents for this purpose include acetone, hexane, ethylacetate, dicholoroethane, chloroform, etc. The extraction isconveniently carried out at moderate temperatures (40-55° C.) and thesolvent is partially removed to yield a concentrate containing 30-60%solids. This solution is cooled to obtain crystals of curcuminoid whichare isolated by any suitable method such as filtration orcentrifugation. Analysis of this product, which is composed of theisolated crystals of curcumioid, showed that 95% of the product wascomposed of curcumin.

The disclosure provides a composition having curcuminoid and anessential oil of turmeric.

Curcumin and the volatile oils of curcumin are mixed and blended to geta uniform product. If small percentages (˜5%) of the essential oil ofturmeric are added to the curcuminoid, then the bioavailability ofcurcumin is significantly enhanced. Accordingly, a composition ofcurcuminoid admixed with a suitable proportion of ar-turmerone (the maincomponent of the turmeric essential oil) is provided.

In some embodiments, the weight ratio of the curcuminoid to theessential oil of turmeric ranges from about 1:1 to about 90:1. In someembodiments, the weight ratio of the curcuminoid to the essential oil ofturmeric ranges from about 1:1 to about 3:1. The weight ratio of thecurcuminoid to the essential oil of turmeric can be varied from about3:1 to about 99:1. In some embodiments, the weight ratio of thecurcuminoid to the essential oil of turmeric ranges from about 1:1 toabout 70:1. In some embodiments, the weight ratio of the curcuminoid tothe essential oil of turmeric ranges from about 1:1 to about 45:1. Insome embodiments, the weight ratio of the curcuminoid to the essentialoil of turmeric ranges from about 3:1 to about 50:1. In someembodiments, the weight ratio of the curcuminoid to the essential oil ofturmeric ranges from about 8:1 to about 25:1. In some embodiments, theweight ratio of the curcuminoid to the essential oil of turmeric isabout 90:7. In some embodiments, the weight ratio of the curcuminoid tothe essential oil of turmeric is about 90:8. In some embodiments, theweight ratio of the curcuminoid to the essential oil of turmeric isabout 90:9. In some embodiments, the weight ratio of the curcuminoid tothe essential oil of turmeric is about 89:9. In some embodiments, theweight ratio of the curcuminoid to the essential oil of turmeric isabout 89:8. In one embodiment, the ratio is about 85:15. In anotherembodiment, the ratio is about 92:8. In another embodiment, the ratio isabout 95:5. In another embodiment the weight ratio is about 10:1. Insome embodiments, the weight ratio of the curcuminoid to the essentialoil of turmeric is about 1:2. In some embodiments, the weight ratio ofthe curcuminoid to the essential oil of turmeric is about 2:1.

In some embodiments of the composition having curcuminoid and addedessential oil of turmeric, the curcuminoid ranges, by weight, from about24% to about 96%. In some embodiments of the composition havingcurcuminoid and added essential oil of turmeric, the curcuminoid ranges,by weight, from about 30% to about 96%. In some embodiments of thecomposition of curcuminoid and added essential oil of turmeric, thecurcuminoid ranges, by weight, from about 40% to about 75%. In someembodiments of the composition having curcuminoid and added essentialoil of turmeric, the curcuminoid ranges, by weight, from about 50% toabout 60%.

In some embodiments of the composition having curcuminoid and addedessential oil of turmeric, the demethoxycurcumin ranges, by weight, fromabout 5% to about 25%. In some embodiments of the composition havingcurcuminoid and added essential oil of turmeric, the demethoxycurcuminranges, by weight, from about 10% to about 20%.

In some embodiments of the enhanced curcumin bioavailability compositionhaving curcuminoid and added essential oil of turmeric, thebisdemethoxycurcumin ranges, by weight, from about 2% to about 7%.

In some embodiments of the enhanced curcumin bioavailability compositionhaving curcuminoid and added essential oil of turmeric, the essentialoil of turmeric ranges, by weight, from about 4% to about 50%. In someembodiments, of the composition of curcuminoid and added essential oilhaving turmeric, the essential oil of turmeric ranges, by weight, fromabout 15% to about 50%. In some embodiments of the composition havingcurcuminoid and added essential oil of turmeric, the essential oil ofturmeric ranges, by weight, from about 20% to about 50%. In someembodiments of the composition having curcuminoid and added essentialoil of turmeric, the essential oil of turmeric ranges, by weight, fromabout 25% to about 40%.

Some embodiments include a composition having a curcuminoid and an addedamount of essential oil of turmeric, wherein the essential oil ispresent in an amount sufficient to cause an enhancement ofbioavailability of the curcumin when administered to a human as comparedto the bioavailability of curcumin upon administration of a compositionprepared using curcuminoid alone without adding essential oil. Curcuminlevels in blood samples is greater following administration of acomposition having curcuminoid and added essential oil of turmeric ascompared to a composition of curcuminoid alone. In some embodiments, theenhancement of bioavailability of curcumin following administration of acomposition of curcuminoid and added essential oil of turmeric rangesfrom about 5-fold to about 16-fold. Enhancement of bioavailability ofcurcumin from a composition prepared by mixing curcuminoid and essentialoil of turmeric is provided in FIG. 1 and Example 1.

In some embodiments, a composition of a curcuminoid and added essentialoil of turmeric is orally administered to a human.

A method of extraction of curcuminoids includes treating dried andpowdered rhizhomes of turmeric with a solvent, followed by solventstripping, and steam distilling to obtain an essential-oil free extract.The essential oil-free extract is cooled to about 4° C. to allow thecurcuminoids to crystallize. The curcuminoids are then separated byfiltration, centrifugation or any other method of solid-liquidseparation well-known in the art. 95% of the separated curcuminoidcrystals are composed of curcumin.

Curcumin is isolated from the de-oiled turmeric by solvent extraction.Suitable solvents for this purpose include acetone, hexane, ethylacetate, dicholoroethane, chloroform, etc. The extraction isconveniently carried out at moderate temperatures (about 40° C. to about55° C.) and the solvent is partially removed to yield a concentratecontaining 30-60% solids. This solution is cooled to obtain crystals ofcurcumin which are isolated by any suitable method such as filtration orcentrifugation. This product was analyzed to contain 95% curcumin. Thepurity of curcumin is 95%; the remaining may contain traces of essentialoil plus other constituents such as carbohydrates, etc, which were notcharacterized.

The disclosure provides a method of extracting a curcuminoid fromturmeric including:

drying rhizomes of turmeric to form a dried turmeric;

powdering the dried turmeric to form a powdered turmeric;

treating the powdered turmeric with a solvent selected from the groupconsisting of ethyl acetate, acetone, hexane, ethylene dichloride, ethylalcohol, and combinations thereof to form a solution;

stripping the solvent from the solution to form an extract;

cooling the extract to about 4° C. to form crystals and a liquid,wherein the liquid comprises the essential oil of turmeric and a resin;and

separating the crystals from the liquid to obtain the curcuminoid, andwherein curcumin comprises 95% of the curcuminoid.

Some embodiments include a method of extracting a curcuminoid fromturmeric by drying rhizomes of turmeric to form dried turmeric. Thedried turmeric is powdered to form powdered turmeric. The powderedturmeric is treated with a solvent selected from the group consisting ofethyl acetate, acetone, hexane, and combinations thereof to form asolution. The solvent is stripped from the solution to form an extract.The extract is cooled to about 4° C. to form crystals of curcuminoid anda liquid, wherein the liquid comprises the essential oil of turmeric anda resin. The crystals of curcuminoid are separated from the liquid toobtain a curcuminoid product, wherein 95% of the curcuminoid product iscomposed of curcumin.

The volatile oil of turmeric was isolated by conventional methods ofsteam distillation to isolate essential oils and is well known in theart.

Curcuminoid and the essential oil are blended in a suitable proportionby a process including, suspending the curcuminoid in about 3 to 5 timesits quantity of water, mixing in the essential oil, pulverizing in acolloidal mill into a fine slurry, and stripping the slurry off waterunder heat and vacuum to obtain a uniform blend. Five hundred milligramcapsules are made from this blend for human consumption.

The disclosure provides a method of preparing a composition including acurcuminoid and an essential oil of turmeric including:

suspending the curcuminoid in water to form a suspension;

adding the essential oil to the suspension to form a mixture;

homogenizing the mixture to obtain a fine slurry; and

drying the fine slurry under heat and vacuum to form a uniform blend ofa composition including the curcuminoid and the essential oil ofturmeric. Drying of the fine slurry under heat and vacuum can beperformed using a vaccumized desolventiser with a stirrer.

A composition of curcuminoid and added essential oil of turmeric can beprepared by suspending the curcuminoid in water to form a suspension.Essential oil is added to the suspension to form a mixture. The mixtureis homogenized to form a fine slurry. The fine slurry is dried underheat and vacuum to form a uniform blend of a composition of curcuminoidand an essential oil of turmeric. The fine slurry can be dried underheat and vacuum using, for example, a vaccumized desolventiser having astirrer.

In one embodiment, a homogeneous mixture of curcuminoid and water isprepared by suspending the curcuminoid in water to form a suspension.The suspension is homogenized to obtain a fine slurry. The fine slurryis dried under heat and vacuum to form a composition having ahomogeneous mixture of the curcuminoid and water.

The disclosure provides a method of preparing a homogeneous mixturehaving a curcuminoid and water by:

suspending a curcuminoid in water to form a suspension;

homogenizing the suspension to obtain a fine slurry; and

drying the suspension under heat and vacuum to form a compositionincluding a homogeneous mixture of the curcuminoid and water.

Biocurcumax gelatin capsules, which contain about 500 mg of a blend ofcurcuminoid and essential oil of turmeric, were prepared. A 500 mgBiocurcumax capsule having the curcuminoid and essential oil of turmericin a weight ratio of about 95:5 is expected to contain about 460 mg ofcurcuminoid, wherein 95% of the curcuminoid is composed of curcumin, andabout 40 mg of essential oil. In terms of active constituents, therespective figures would be about 437 mg of curcumin and about 18 mg ofar-turmerone. In some embodiments, the Biocurcumax gelatin capsules haveabout 300 mg to about 460 mg of curcuminoid and about 40 mg to about 200mg of essential oil of turmeric. In some embodiments of the compositionhaving curcumin and added essential oil of turmeric, wherein the gelatincapsule comprises 500 mg of a blend including the curcuminoid and theessential oil, the curcuminoid in the blend ranges from about 300 mg toabout 485 mg, and the ar-turmerone in the blend ranges from about 5 mgto about 200 mg.

Gelatin capsules with curcuminoid alone but without added essential oilwere similarly prepared to study the comparative efficacies of thecapsule containing added essential oil versus the capsule preparedwithout adding essential oil.

The disclosure provides a method of preparing a gelatin capsule having acurcuminoid and an essential oil of turmeric by:

suspending a curcuminoid in water to form a suspension;

adding an essential oil to the suspension to form a mixture;

homogenizing the mixture to obtain a fine slurry;

drying the slurry under heat and vacuum to form a uniform blend of acomposition having the curcuminoid and the essential oil; and

compressing the blend into the gelatin capsule.

Gelatin capsules of a composition having a curcuminoid and an addedessential oil of turmeric can be prepared by compressing a uniform blendof the composition into a capsule. Gelatin capsules are prepared bystandard methods using instrument such as a capsule filling machinemanufactured by Pam Pharmaceuticals, Mumbai, India.

The disclosed compositions can be administered to a human for treatingconditions including various human cancers such as colon cancer,prostate cancer, breast cancer, lung cancer, oral cancers, leukemias,etc, and various chronic inflammatory diseases such as rheumatoidarthritis, Alzheimer's disease, inflammatory bowel diseases (Crohn'sdisease, ulcerative colitis), coronary artery diseases, fibrosis andcirrhosis of liver, pancreatitis, and central nervous system disorders.

The inventive compositions have the additional benefit that theessential oil components are themselves bioactive (for example, see Yue,A et al, Int. J. Mol. Med., 2002, 9:481-84; Jayaprakasha, G. K. et al,Z. Naturforsch., 2002, 57:828-35) and thus are expected tosynergistically enhance the bioactivity of curcumin.

It will be readily understood by the skilled artisan that numerousalterations may be made to the examples and instructions given herein.These and other objects and features of present invention will be madeapparent from the following examples. The following examples asdescribed are not intended to be construed as limiting the scope of thepresent invention.

EXAMPLES Example 1

Nine healthy human volunteers aged between 25 and 45 years of age wereselected for the study. They were given curcuminoid and enhancedcurcumin, which is also referred to as Biocurcumax or a compositionhaving curcuminoid and added essential oil of turmeric, capsules at thedosage of 50 mg curcuminoid/kg body weight. In the enhanced curcumincapsules (or Biocurcumax) the weight ratio of curcuminoid to essentialoil of turmeric was 10:1. They were advised to take curcuminoid capsulesfirst. Blood samples were collected at zero hour and periodically atone-hour or half-hour intervals for 8 hours. After a washout period ofone week, the same protocol was repeated with enhanced curcuminbioavailability (Biocurcumax) capsules. The whole blood was extractedexhaustively with ethyl acetate to recover curcumin. The ethyl acetateextract was analyzed by HPLC on a RP-C18 column (25×4.5 mm) usingmethanol as solvent and UV detection at 420 nm. The eluant flow rate was1 ml/min. Efficiency of the extraction procedure for recovering curcuminfrom blood samples was determined by measuring recovery of curcumin uponextraction of normal blood samples. Normal blood samples were collectedby adding curcumin to normal blood (of persons not consuming curcumin orenhanced curcumin capsules). Curcumin was extracted from the normalblood samples by the above procedure. The efficiency of recovery ofcurcumin by the above extraction procedure was estimated to rangebetween 80.12% and 86.49%.

A typical result is given in Table 1.

TABLE 1 Curcumin content in blood (ng/g) Enhanced curcuminbioavailability Time Curcumin composition (h) composition (Biocurcumax)0.0 0.0 0.0 0.5 3.17 7.85 1.0 7.57 6.23 1.5 4.42 4.84 2.0 13.81 11.952.5 9.61 19.22 3.0 5.67 92.59 4.0 8.2 24.33 6.0 1.62 8.43 8.0 1.11 5.09

The results are also graphically represented in FIG. 1. The peakabsorption of curcumin from Biocurcumax occurred at 3 hr, furthermore,curcumin persisted in small amounts in the blood till 8 hr beyond whichmeasurements were not made. At peak absorption the enhancement ofbioavailability ranged, among the 9 persons, between 5 and 16-fold witha mean value of 10.62.

Example 2

Human subjects were administered capsule (4×500 mg) prepared withcurcuminioids and without added essential oil of turmeric (curcuminoidsgroup in Table 2). Blood was drawn at different intervals (one hour) andtested for curcumin content. After two weeks the same groups wereadministered an enhanced curcumin bioavailability composition, referredto as Biocurcumax capsules (4×500 mg). The varying ratios ofcurcuminoids and added essential oil of turmeric are as provided inTable 2. Blood from the Biocurcumax group was drawn at differentintervals and tested for curcumin content. As seen in Table 2,bioavailability of curcumin was greater when Biocurcumax capsules wereadministered as compared to administration of capsule containingcurcuminoids without added essential oil of turmeric.

TABLE 2 Analysis of curcumin content in blood. Ratio of curcuminoids toadded Curcumin content in blood (AUC) essential oil CurcuminoidsBiocurcumax of turmeric group group 90:4 725 5147.5 90:5 820 5904 90:6750 5475 90:7 900 6300.0 90:8 752 5367.6 90.9 782 5552.2 89.9 696 5080.890:10 760 5320 80:9 726 5227.2 80:20 754 5315.7 90:20 765 5469.75 70:20810 5147.5

The ratios of curcuminoids to added essential oil of turmeric in theenhanced curcumin bioavailability composition provided in Table 2 canalso be represented as shown in Table 3. The units of curcumin contentin blood is provided as area under the curve (AUC).

TABLE 3 Ratio of curcuminoids to added essential oil in compositions forenhanced curcumin bioavailability Ratio of Ratio of Curcuminoidscurcuminoids to added to added essential oil essential oil of turmericof turmeric 90:4  22.5:1 90:5   18:1 90:6   15:1 90:7  12.9:1 90:811.25:1 90:9   10:1 90:10    9:1 80:9  8.9:1 80:20    4:1 90:20  4.5:170:20   35:1

Other modifications and variations to the invention will be apparent tothose skilled in the art from the foregoing disclosure and teachings.Thus, while only certain embodiments of the invention have beenspecifically described herein, it will be apparent that numerousmodifications may be made thereto without departing from the spirit andscope of the invention.

What is claimed is:
 1. A method of obtaining a blood curcuminconcentration of about 92 ng/g in a human subject, the method comprisingadministering a composition for enhanced bioavailability of curcumin tothe human subject, wherein the composition for enhanced bioavailabilityof curcumin comprises a curcuminoid mixture and the essential oil ofturmeric, wherein a weight ratio of the curcuminoid mixture to the addedessential oil of turmeric ranges from about 1:3 to about 99:1, whereinthe curcuminoid mixture consists of curcumin, demethoxycurcumin andbisdemethoxycurcumin, and wherein the essential oil of turmericcomprises about 45% ar-turmerone.
 2. The method of claim 1, wherein theblood curcumin concentration of about 92 ng/g in the human subject isreached about 3 hours after administering the composition for enhancedbioavailability of curcumin.
 3. A method of enhancing bioavailability ofcurcumin in a human subject, the method comprising administering acomposition for enhanced bioavailability of curcumin, wherein thecomposition for enhanced bioavailability of curcumin comprises acurcuminoid mixture and the essential oil of turmeric, wherein a weightratio of the curcuminoid mixture to the added essential oil of turmericranges from about 1:3 to about 99:1, wherein the curcuminoid mixtureconsists of curcumin, demethoxycurcumin and bisdemethoxycurcumin, andwherein the essential oil of turmeric comprises about 45% ar-turmerone.4. The method of enhancing bioavailability of curcumin in the humansubject of claim 3, wherein administering the composition for enhancedbioavailability of curcumin results in about 5-fold to about 16-foldenhancement of curcumin concentration in the human subject as comparedto administering a composition comprising the curcuminoid mixturewithout the added essential oil of turmeric.
 5. The method of claim 3,wherein a blood curcumin concentration of about 92 ng/g is observed atabout 3 hours following administration of the composition for enhancedbioavailability of curcumin.
 6. The method of claim 3, wherein a bloodcurcumin concentration of about 5 ng/g is observed at about 8 hoursfollowing administration of the composition for enhanced bioavailabilityof curcumin.
 7. A method of obtaining a blood curcumin concentration ofabout 5 ng/g in a human subject, the method comprising administering acomposition for enhanced bioavailability of curcumin to the humansubject, wherein the composition for enhanced bioavailability ofcurcumin comprises a curcuminoid mixture and the essential oil ofturmeric, wherein a weight ratio of the curcuminoid mixture to the addedessential oil of turmeric ranges from about 1:3 to about 99:1, whereinthe curcuminoid mixture consists of curcumin, demethoxycurcumin andbisdemethoxycurcumin, and wherein the essential oil of turmericcomprises about 45% ar-turmerone.
 8. The method of claim 7, wherein theblood curcumin concentration of about 5 ng/g in the human subject isreached about 8 hours after administering the composition for enhancedbioavailability of curcumin.